- Site-Selective Installation of N?-Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C–C Bond Formation
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Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site-specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp3)–C(sp3) bond forming reaction that enables the site-selective installation of N?-modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site-selectively installing an N?Ac sidechain into recombinantly expressed ubiquitin (Ub).
- Griffiths, Rhys C.,Layfield, Robert,Long, Jed E.,Mitchell, Nicholas J.,Oldham, Neil J.,Scott, Daniel,Smith, Frances R.,Williams, Huw E. L.
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supporting information
(2021/12/08)
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- Catalyst freeN-formylation of aromatic and aliphatic amines exploiting reductive formylation of CO2using NaBH4
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Herein, we report a sustainable approach forN-formylation of aromatic as well as aliphatic amines using sodium borohydride and carbon dioxide gas. The developed approach is catalyst free, and does not need pressure or a specialized reaction assembly. The reductive formylation of CO2with sodium borohydride generates formoxy borohydride speciesin situ, as confirmed by1H and11B NMR spectroscopy. Thein situformation of formoxy borohydride species is prominent in formamide based solvents and is critical for the success of theN-formylation reactions. The formoxy borohydride is also found to promote transamidation reactions as a competitive pathway along with reductive functionalization of CO2with amine leading toN-formylation of amines.
- Kumar, Arun,Kumar, Yashwant,Mahajan, Dinesh,Sharma, Nidhi,Sharma, Pankaj
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p. 25777 - 25787
(2021/08/05)
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- KOtBu-Promoted Transition-Metal-Free Transamidation of Primary and Tertiary Amides with Amines
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This work discloses transamidation of primary and tertiary amides with a range of aryl, heteroaryl, and aliphatic amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions providing secondary amides in high yields. Moreover, reaction of cyclopropyl amine with tertiary amides proceeds with ring-opening to provide a rapid access to enamides.
- Ghosh, Tridev,Jana, Snehasish,Dash, Jyotirmayee
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supporting information
p. 6690 - 6694
(2019/09/12)
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- A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N-Substituents
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The multicomponent backbone N-modification of peptides on solid-phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N-substituents suitable for backbone stapling can be readily introduced by means of on-resin Ugi multicomponent reactions conducted during solid-phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N-substituents, including the ring-closing metathesis, lactamization, and thiol alkylation. The backbone N-modification method was also applied to the synthesis of α-helical peptides by linking N-substituents to the peptide N-terminus, thus featuring hydrogen-bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.
- Ricardo, Manuel G.,Marrrero, Javiel F.,Valdés, Oscar,Rivera, Daniel G.,Wessjohann, Ludger A.
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supporting information
p. 769 - 774
(2019/01/04)
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- Mild Access to N-Formylation of Primary Amines using Ethers as C1 Synthons under Metal-Free Conditions
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A new synthetic protocol has been developed for the synthesis of N-formamide derivatives using ethers as a C1 synthon under metal-free reaction conditions. The reaction is proposed to proceed through C?H functionalization, C?O cleavage, and C?N bond formation. This protocol is applicable to a variety of primary amines resulting in N-formamides in moderate to good yields. 1,4-dioxane was chosen as best C1 synthon after screening with various ethers. Mechanistic studies disclosed that the reaction proceeds through a radical pathway. While using α-amino ketones a α-alkylation product was formed rather than formylation. By replacing dioxane with Tetramethylethylenediamine (TMEDA) under standard conditions also gave the N-formamide derivatives in moderate yields. (Figure presented.).
- Mutra, Mohana Reddy,Dhandabani, Ganesh Kumar,Wang, Jeh-Jeng
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supporting information
p. 3960 - 3968
(2018/09/10)
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- Chemoselective Schwartz Reagent Mediated Reduction of Isocyanates to Formamides
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Addition of the in situ generated Schwartz reagent to widely available isocyanates constitutes a chemoselective, high-yielding, and versatile approach to the synthesis of variously functionalized formamides. Steric and electronic factors or the presence of sensitive functionalities (esters, nitro groups, nitriles, alkenes) do not compromise the potential of the method. Full preservation of the stereochemical information contained in the starting materials is observed. The use of formamides in the nucleophilic addition of organometallic reagents (Chida-Sato allylation, Charette-Huang addition to imidoyl triflate activated amides, Matteson homologation of boronic esters) is briefly investigated.
- Pace, Vittorio,De La Vega-Hernández, Karen,Urban, Ernst,Langer, Thierry
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supporting information
p. 2750 - 2753
(2016/06/15)
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- Palladium-Catalyzed Synthesis of Allylic Ureas via an Isocyanate Intermediate
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A palladium-catalyzed coupling of allylic carbonates with trimethylsilylisocyanate to provide allylic isocyanates is reported. Amines are added in a second step to yield allylic ureas in this one-pot procedure. Use of a bidentate phosphine ligand with a large bite angle was found to be important in this transformation. The scope of allylic carbonates has been examined, as well as amines compatible with these reaction conditions.
- Jay, Lucien P.,Barker, Timothy J.
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p. 1829 - 1831
(2016/05/09)
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- Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions
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A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Br?nsted acidity of acetic acid. Amide bonds are reputedly difficult to activate due to their high resonance stabilization. An unusual mild activation of dimethylformamide and formamide by borinic acid 1 (see scheme), illustrated by a general formylation of a wide range of amines, including chiral α-amino esters, has been reported.
- Mohy El Dine, Tharwat,Evans, David,Rouden, Jacques,Blanchet, Jér?me
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supporting information
p. 5894 - 5898
(2016/04/26)
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- A Modular Formal Total Synthesis of (±)-Cycloclavine
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Cycloclavine is a clavine-type Ergot alkaloid noteworthy for its unique pentacyclic skeleton featuring a 3-azabicyclo[3.1.0]hexane substructure. A short convergent route to the racemic alkaloid is described which comprises only eight linear steps and requires only four chromatographic purifications. The two key building blocks can be prepared in high yield from commercially available starting materials. Two consecutive coupling reactions, namely a selective alkylation of a dienolate and a Heck reaction, are the key steps of the reaction sequence. (Chemical Equation Presented).
- Netz, Natalie,Opatz, Till
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p. 1723 - 1730
(2016/03/01)
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- Synthesis and characterization of novel carbene complexes of phosphorus(V) fluorides with potential liquid-crystalline properties
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A series of novel push-push I and push-pull II carbene-stabilized complexes of phosphorus(V) fluorides bearing substituents with liquid-crystalline properties were synthesized by the oxidative addition of difluoroamines to phosphorus(III) halides. These octahedral complexes were characterized by NMR spectroscopy and X-ray analysis.
- Pajkert, Romana,B?ttcher, Tobias,Ponomarenko, Maksym,Bremer, Matthias,R?schenthaler, Gerd-Volker
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p. 8943 - 8951
(2013/09/23)
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- Substrate-directable heck reactions with arenediazonium salts. The regio- and stereoselective arylation of allylamine derivatives and applications in the synthesis of naftifine and abamines
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The palladium-catalyzed, substrate-directable Heck-Matsuda reaction of allylamine derivatives with arenediazonium salts is reported. The reaction proceeds under mild conditions, with excellent regio- and stereochemical control as a function of coordinating groups present in the allylamine substrate. The distance between the olefin moiety and the car-bonylic system seems to play a key role regarding the regiocontrol. The method presents itself as robust, as simple to carry out, and with wide synthetic scope concerning the allylic substrates and the type of arenediazonium employed. The synthetic potential of the method is illustrated by the short total syntheses of the bioactive compounds naftifine, abamine, and abamine SG.
- Prediger, Patricia,Barbosa, Lais Ferreira,Genisson, Yves,Correia, Carlos Roque Duarte
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experimental part
p. 7737 - 7749
(2011/12/01)
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- N-carbonylation of lithium azaenolates of amides, formamides, ureas, and carbamates with carbon monoxide mediated by selenium
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N-Carbonylation of less nucleophilic nitrogen compounds was achieved by the reaction of the lithium azaenolates with carbon monoxide and selenium. This reaction proceeds in the cases of amides, formamides, ureas, and carbamates, leading to the formation of the corresponding carbamosele-noates in good to high yields after trapping with BuI.
- Fujiwara, Shin-Ichi,Okada, Kazuhiro,Shikano, Yasukazu,Shimizu, Yoshihiko,Tsutomu, Shin-Ike,Terao, Jun,Kambe, Nobuaki,Sonoda, Noboru
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p. 273 - 276
(2007/10/03)
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- 5-amino-4-hydroxyhexanoic acid derivatives
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Compounds of formula I STR1 or their hydroxy-protected derivatives, and compounds of formula I' STR2 wherein T is an acyl radical of formula Z STR3 wherein Rz is unsubstituted or substituted hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical Rz is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl, aryl or unsubstituted or substituted amino, and wherein the radicals R1, B1, R2, R3, A1, A2 and NR4 R5 are as defined in the description, and precursors thereof, are described. The compounds have pharmaceutical activity, for example in the treatment of retroviral diseases, such as AIDS.
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- Overtone-induced isomerization of allyl isocyanide
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The rate of isomerization of allyl isocyanide to allyl cyanide is monitored using Stern-Volmer kinetics when various features of the 5-O and 6-O C-H overtone stretch region are excited.Previously, Reddy and Berry found that the isomerization rates varied from band to band and that the variations were not monotonic with excitation energy.They attributed this behavior to nonstatistical effects.It is found in this study that the isomerization rates vary within an overtone band by up to a factor of 1.8, in addition to the variations from band to band seen previously.This observation rules out the possibility that the overtone bands are purely lifetime broadened.In addition, the photoisomerization rate increases with increasing temperature.An increase of 60 K increases the photolysis yield in the 5-O C-H region by a factor of 3-4, while increases in the 6-O C-H region are smaller, 25percent-60percent.These effects can be qualitatively explained if the overtone spectrum of allyl isocyanide is inhomogeneously broadened because of the presence of vibrational "hot bands." In this case, molecules excited by the photolysis laser will have varying amounts of initial thermal energy depending on where the laser is tuned within a band.A simple model for the effects of hot bands on the isomerization rate is in good agreement with experimental results.It is not necessary to invoke nonstatistical effects in order to explain the observed overtone-pumped isomerization rates of allyl isocyanide.
- Segall, Jeffrey,Zare, Richard N.
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p. 5704 - 5714
(2007/10/02)
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- N-Alkyl-N-iminomethyl derivatives of thienamycin
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Disclosed are N-alkyl-N-iminomethyl derivatives of thienamycin which may be represented by the following structural formula: STR1 wherein R5 is, inter alia, alkyl, alkenyl, aryl, or aralkyl, R6 is selected from R, OR, SR and NR1
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- Substituted N-methylene derivatives of thienamycin
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Disclosed are substituted N-methylene derivatives of thienamycin which may be represented by the following structural formula: STR1 wherein X and Y are selected from the group consisting of hydrogen, R, OR, SR, and NR1 R2 wherein, in
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- Substituted N-methylene derivatives of thienamycin sulfoxide and sulfone
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Disclosed are substituted N-methylene derivatives of thienamycin sulfoxide (I, n=1) and sulfone (I, n=2) which may be represented by the following structural formula: STR1 wherein X and Y are selected from the group consisting of hydrogen, R, OR, SR, and NR1 R2 wherein, inter alia, R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; R1 and R2 are hydrogen or R. Such compounds and their pharmaceutically acceptable salt, ether, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
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